A Convenient Synthetic Method of a 5,7-Diarylcyclopenteno-[1,2- b]pyridine-6-carboxylate: A Key Intermediate for Potent Endothelin Receptor Antagonists

• Published in: Bioorganic & medicinal chemistry 2002-11, Vol.10 (11), p.3437-3444
• Main Authors: Niiyama, Kenji, Yoshizumi, Takashi, Takahashi, Hirobumi, Naya, Akira, Ohtake, Norikazu, Fukami, Takehiro, Mase, Toshiaki, Hayama, Takashi, Ishikawa, Kiyofumi
• Format: Article
• Language: English
• Subjects: Carboxylic Acids - chemical synthesis; Catalysis; Chemistry; Endothelin Receptor Antagonists; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indicators and Reagents; Keto Acids - chemistry; Organic chemistry; Preparations and properties; Pyridines - chemical synthesis; Solvents; Stereoisomerism; Zinc - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(02)00261-4

A convenient synthetic method of 4, a key intermediate for a new class of endothelin receptor antagonists, was developed. Racemic 4 was synthesized from quinolinic anhydride in 13.4% overall yield without chromatographic purification. A convenient method for the synthesis of the title intermediate 4 was described. The key steps of this synthesis involved: (1) regioselective addition reaction of arylzinc reagent to quinolic anhydride in 42% isolated yield, (2) conversion of a ketoacid 7 to an enone 14 , which was achieved in 65% yield by intramolecular Knoevenagel reaction of β-ketoester generated by condensation of an acid imidazolide 11 with an ester enolate, followed by dehydration assisted with silica gel, and (3) stereoselective reduction of an allyl alcohol 15 in 75% yield with zinc under acidic conditions. This synthesis enabled us to provide hundreds of grams of 4 without chromatographic purification.